Remimazolam, the chemical name of which is methyl 3-[(4s)-8-bromo-1-methyl-6-(2-pyridyl)-4H-imidazol[1,2-a][1,4]benzodiazepine-4-yl] propionate, has the structure represented by formula (I):

The compound is currently known to be a short-acting Central Nervous System (CNS) inhibitor with sedative, hypnotic, anxiolytic, muscle-relaxing and anticonvulsant effects. At present, it is mostly used for intravenous administration in the following clinical treatment regimens: for pre-operative sedation, anxiolytic and amnestic use during surgery; for conscious sedation during short-term diagnosis, surgery or endoscopic procedures; as a component for induction and maintenance of general anesthesia before and/or at the same time of administering other anesthetics and analgesia; for ICU sedation and the like. It is reported in the patent application CN101501019 that the free base of the compound has poor stability, and is only suitable for storage at a low temperature of 5° C., and, under the condition of 40° C./75% relative humidity (open), the sample is deliquescent, discolored, and significantly reduced in content.
In view of the stability problem with the free base of the compound, salts of the compound have been studied by researchers in multiple countries. For example, the patent applications CN101501019B and WO2008/007081 A1 respectively reported besylate and esylate of the compound of the formula (I). It is shown that the above salts have good thermal stability, low hygroscopicity and high water solubility. Moreover, CN104968348A clearly indicated that the above-mentioned besylate and esylate are the most preferred salts of the compound of the formula (I).
Immediately thereafter, CN103221414B proposed a tosylate of the compound of the formula (I), and indicated that the tosylate is less toxic than besylate, and some crystal forms thereof behave better in thermal stability, water solubility, etc.
By sorting the prior art information, the following related contents can be obtained (Table 1):
TABLE 1NameCompanyPatent No.PropertiesRemimazolamPAIONCN200780028964.5Solubility in water: 8.3 mg/ml; degradation 0.5% at 40besylateCN201310166860.8degrees, RH75% closed, 4 weeks(CNS-7056)RemimazolamJiangsuCN201280003321.6Solubility in water: about 10, 11 mg/ml; influence factortosylate (HR-7056)Hengruitests show that the most stable crystal form still behavesnot ideal under light conditions, with degradation morethan 1.5% in 10 days. The patent states that the salt isless toxic than benzene sulfonic acidRemimazolamCambridge(GB)US20100075955Solubility in water: 7.8 mg/ml; degradation 0.2% at 40esylatedegrees, RH75% closed, 4 weeksRemimazolamGSKWO 00/69836Almost insoluble in water; degradation 1.5-8%, andyellowing at 40 degrees, RH75% closed and 60 degreesopen, 34 days
It can be seen from the above table, neither the free base of remimazolam nor known salt derivatives of remimazolam has a water solubility higher than 11 mg/ml. The solubility is only in the range of sparingly soluble, which will increase its safety risk in clinical use, and require long-term vibration dissolution during clinical redissolution, and may also leave insoluble materials, resulting in inaccurate drug dosage and potential safety risks. In addition, when used for indications which require a large amount of drug, such as general anesthesia, the amount of diluent will be increased, resulting in extreme inconvenience in clinical use. Therefore, the solubility of known salt derivatives of remimazolam is a major disadvantage and needs to be further improved.